Mitochondrial response to hyperthermia : the catastrophe starts above the febrile temperature

Abstract

We applied modular kinetic analysis to study the response of oxidative phosphorylation system in rat heart mitochondria (Mt) to different regimes of hyperthermic treatment. Increasing temperature in the febrile range (37–41oC) slightly activated Mt function due to the stimulation of the respiratory subsystem but the kinetics of proton leak and the phosphorylation subsystem was not affected. Higher temperatures (42–45oC), exceeding the febrile range induced different pattern of changes - severe impairment of the energy transforming function of Mt. The effect was caused by the sudden loss of the membrane barrier function that started at 42oC. Although at this temperature state 3 respiration rate remained unchanged, the proton leak was substantially increased, the respiratory subsystem - slightly inhibited, and the membrane potential (Dw) dropped from 148±3 to 140±3 mV, leading to partial uncoupling of oxidative phosphorylation and the diminished ATP synthesis (16% lower phosphorylation flux). Further increase of temperature is extremely harmful for Mt function mostly because of induced changes in membrane properties: after three minutes of incubation at 43 and 45oC Mt become completely uncoupled and are not able to maintain Dw and to phosphorylate. These effects are not reverted by cyclosporin A. Our findings help to understand Mt behaviour under different regimes of hyperthermic treatment applied for healthy and tumour tissues.